This proposal attempts to address whether a newly discovered molecule called Dicer, responsible for RNA silencing, is required for the development and function of the immune system. Towards this overall aim, we are well underway in creating a genetically-engineered mouse in which the gene for Dicer can be conditionally deleted in a cell-type, stage specific and/or temporal manner. First, this molecule may be required for the development of the immune system since it is required for organ development in lower organisms such as the fruit fly. Specifically, we wish to determine whether Dicer is required for normal lymphocyte development. One hypothesis is that it may regulate V(D)J recombination by modulating the chromatin structure of immunoglobulin and T cell receptor genes. Second, we wish to determine whether micro-RNAs processed by Dicer may also regulate development of the immune system, particularly the maintenance of hematopoietic stem cells. Third, we wish to determine whether Dicer has a role in anti-viral immunity by virtue of its intrinsic capability to sense and eliminate viral RNA, as in plants. Dicer may be part of an ancient immune system that detects and protects us against viruses. This line of research may provide novel immunotherapeutic avenue to combat certain viruses. [unreadable] [unreadable]